Background and Aim The study of CD44/CD24 and ALDH1 expression is the most accurate method to identify cancer stem cells (CSC) from breast cancer populations. However, the overlap between CD44 + CD24À/low and ALDH1 high CSC phenotypes in breast cancer seems to be very small, as well as their distribution among intrinsic breast cancer subtypes. Due to this discrepancy, it is imperative to improve the understanding of breast CSC marker distribution. Methods 466 invasive breast carcinomas and eight breast cancer cell lines were analysed for the expression of CD44, CD24 and ALDH1, to evaluate their distribution among the distinct molecular subtypes. Results Basal-like tumours (76.5%) contained the higher percentage of cells with the CSC phenotype CD44 +
P-cadherin overexpression is associated with worse breast cancer survival, being a poor prognostic marker as well as a putative therapeutic target for the aggressive triple-negative and basal-like carcinomas (TNBCs). Previously, we have shown that P-cadherin promotes breast cancer invasion of cells where membrane E-cadherin was maintained; however, it suppresses invasion in models without endogenous cadherins, like melanomas. Here, we investigated if P-cadherin expression would interfere with the normal adhesion complex and which were the cellular/molecular consequences, constituting, in this way, a new mechanism by which E-cadherin invasive-suppressor function was disrupted. Using breast TNBC models, we demonstrated, for the first time, that P-cadherin co-localizes with E-cadherin, promoting cell invasion due to the disruption caused in the interaction between E-cadherin and cytoplasmic catenins. P-cadherin also induces cell migration and survival, modifying the expression profile of cells expressing wild-type E-cadherin and contributing to alter their cellular behaviour. Additionally, E- and P-cadherin co-expressing cells significantly enhanced in vivo tumour growth, compared with cells expressing only E- or only P-cadherin. Finally, we still found that co-expression of both molecules was significantly correlated with high-grade breast carcinomas, biologically aggressive, and with poor patient survival, being a strong prognostic factor in this disease. Our results show a role for E- and P-cadherin co-expression in breast cancer progression and highlight the potential benefit of targeting P-cadherin in the aggressive tumours expressing high levels of this protein.
Background: TP53 is one of major tumour suppressor genes being essential in preservation of genome integrity. Two very common polymorphisms have been demonstrated to contribute to cancer susceptibility and tumour behaviour. The purpose of this study was to evaluate the role of Arg72Pro and PIN3 Ins16bp polymorphisms in TP53 gene as genetic susceptibility and predictive markers to breast cancer.
Solid cell nests of the human thyroid gland are composed of main cells and C cells. In order to investigate the putative stem cell nature of the role for solid cell nests, we evaluated the histological features, and the immunohistochemical expression of p63, bcl-2, telomerase catalytic subunit, and two proliferative markers (Ki-67 and minichromosome maintenance protein 2), in a series of 24 cases of solid cell nests. Proliferative indices were determined in (a) solid cell nests, (b) thyroid follicular cells in the vicinity of solid cell nests within a low-power field, and (c) distant thyroid tissue, at a distance of at least three low-power fields from solid cell nests. In 15 cases of solid cell nests (62.5%), mixed follicles were observed; papillary formations were observed in four cases (16.6%), and ciliated cells were observed in the lining of microcysts associated with two cases (8.3%). Salivary gland-type tissue, cartilage islands, adipose and fibrous tissues, and small nerves were also associated with some cases of solid cell nests. We observed that the main cells of the solid cell nests express consistently telomerase, although at lower levels than p63, and show strong cytoplasmic immunoreactivity for bcl-2, which is associated with an increased differentiation potential. We also observed that despite their relative low proliferative index, main cells of the solid cell nests display higher proliferation than follicular cells in the vicinity and follicular cells in more distant thyroid tissue. We conclude that main cells of the solid cell nests apparently harbor the minimal properties of a stem cell phenotype (capacity for both self-renewal, conferred by telomerase activity, and differentiation to one or more than one type of specialized cells, given by the high expression of p63 and bcl-2) and may thus represent a pool of stem cells of the adult thyroid.
Although the luminal progenitor cell of the normal mammary gland hierarchy has been proposed as the cell-of-origin for basal-like breast cancers, finding the cancer stem cell (CSC) phenotype for this malignancy has proven a difficult task, mostly due to the lack of specific markers. Recently, basal-like sporadic and familial cases of breast cancer have been linked to BRCA1 gene inactivation, which enables the upregulation of the target-repressed CDH3/P-cadherin gene, an important biomarker of basallike breast carcinomas. Previously, we demonstrated that P-cadherin overexpression can mediate aggressive behavior in these tumors. Thus, our aim was to test whether P-cadherin mediates stem cell properties in basal-like breast carcinomas. Using a series of breast cancer cell lines and primary tumors, we showed that P-cadherin was directly associated with the expression of the breast stem markers CD44, CD49f, and aldehyde dehydrogenase 1 in the basal subtype. Moreover, cell population enriched for P-cadherin expression comprised increased in vitro mammosphere-forming efficiency and capacity to grow colonies in three-dimensional cultures as well as greater tumorigenicity. Importantly, an association was found with stem-/ progenitor-like phenotypes of the breast, including the luminal progenitor population, CD49f 1 CD24 1 . Additionally, P-cadherin expression conferred resistance to x-rayinduced cell death, sustaining a role for this molecule in another stem cell property. In summary, we demonstrated, for the first time, that P-cadherin mediates stem cell properties, which could be explored in order to better define the CSC phenotype of basal-like breast tumors and the cell-of-origin of this malignancy. STEM CELLS 2012;30:854-864 Disclosure of potential conflicts of interest is found at the end of this article.
The purpose of this study was to evaluate the role of polymorphisms in DNA repair genes as genetic indicators of susceptibility to familial and sporadic breast cancer. We analysed DNA samples from 285 breast cancer patients and 442 control subjects, for XRCC1 Arg399Gln, XPD Lys751Gln, RAD51 G135C and XRCC3 Thr241Met polymorphisms using PCR-RFLP. We observed that women carriers of XRCC1 399Gln genotypes and without family history of breast cancer have a protective effect concerning this disease (OR = 0.54 95% CI 0.35-0.84; p = 0.006). Furthermore, we found that carriers of XRCC3 241Met genotypes without FH have an increased susceptibility of breast cancer (OR = 2.21 95% CI 1.42-3.44; p < 0.001). Additionally, we verified an increased risk of breast cancer in women with FH and carrying RAD51 135C genotypes (OR = 2.17 95% CI 1.19-3.98; p = 0.012). Our results suggest XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair polymorphisms as important biomarkers to sporadic breast cancer susceptibility, as well as, RAD51 G135C polymorphism as a real risk modifier in familial breast cancer cases.
BackgroundA breast cancer prognostic tool should ideally be applicable to all types of invasive breast lesions. A number of studies have shown histopathological grade to be an independent prognostic factor in breast cancer, adding prognostic power to nodal stage and tumour size. The Nottingham Prognostic Index has been shown to accurately predict patient outcome in stratified groups with a follow-up period of 15 years after primary diagnosis of breast cancer. Clinically, breast tumours that lack the expression of Oestrogen Receptor, Progesterone Receptor and Human Epidermal growth factor Receptor 2 (HER2) are identified as presenting a "triple-negative" phenotype or as triple-negative breast cancers. These poor outcome tumours represent an easily recognisable prognostic group of breast cancer with aggressive behaviour that currently lack the benefit of available systemic therapy. There are conflicting results on the prevalence of lymph node metastasis at the time of diagnosis in triple-negative breast cancer patients but it is currently accepted that triple-negative breast cancer does not metastasize to axillary nodes and bones as frequently as the non-triple-negative carcinomas, favouring instead, a preferentially haematogenous spread. Hypothetically, this particular tumour dissemination pattern would impair the reliability of using Nottingham Prognostic Index as a tool for triple-negative breast cancer prognostication.MethodsThe present study tested the effectiveness of the Nottingham Prognostic Index in stratifying breast cancer patients of different subtypes with special emphasis in a triple-negative breast cancer patient subset versus non- triple-negative breast cancer.ResultsWe demonstrated that besides the fact that TNBC disseminate to axillary lymph nodes as frequently as luminal or HER2 tumours, we also showed that TNBC are larger in size compared with other subtypes and almost all grade 3. Additionally, survival curves demonstrated that these prognostic factors are equally important to stratify different survival outcomes in non-TNBC as in TNBC. We also showed that the NPI retains the ability to stratify and predict survival of TNBC patients.ConclusionThe importance of this study relies on the need of prognostication improvements on TNBC, showing, at a clinical standpoint, that Nottingham Prognostic Index is as a truthful prognostic tool in TNBC.
Results indicate that p120-catenin cytoplasmic accumulation may play an important role in mediating the oncogenic effects derived from P-cadherin aberrant expression, including enhanced motility and invasion, particularly in tumours which maintain E-cadherin expression.
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